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WO2006004917A2 - Methode de traitement de cancer du sein au moyen d'un melange d'analogues de vitamine d et d'autres agents - Google Patents

Methode de traitement de cancer du sein au moyen d'un melange d'analogues de vitamine d et d'autres agents Download PDF

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Publication number
WO2006004917A2
WO2006004917A2 PCT/US2005/023259 US2005023259W WO2006004917A2 WO 2006004917 A2 WO2006004917 A2 WO 2006004917A2 US 2005023259 W US2005023259 W US 2005023259W WO 2006004917 A2 WO2006004917 A2 WO 2006004917A2
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WIPO (PCT)
Prior art keywords
agent
cells
administered
dihydroxyvitamin
vitamin
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PCT/US2005/023259
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English (en)
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WO2006004917A3 (fr
Inventor
Stephen A. Strugnell
Don Wigington
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Bone Care International, Inc.
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Publication of WO2006004917A2 publication Critical patent/WO2006004917A2/fr
Publication of WO2006004917A3 publication Critical patent/WO2006004917A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates generally to a method of treating hyperproliferative diseases, particularly breast cancer.
  • the method of the invention uses active compounds of vitamin D in combination with other agents to inhibit the hyperproliferative cellular activity of these diseases and to promote differentiation of the cells.
  • Breast cancer is the most commonly diagnosed cancer in women in both United States and worldwide. Breast cancer rates are the highest in industrialized countries. In the United States, the incidence of breast cancer has more than doubled in the past 30 years. In 1964, the lifetime risk was 1 in 20. Today it's 1 in 8. Approximately 185,700 new cases are diagnosed in the U.S. annually, and breast cancer is responsible for about 44,560 deaths in the U.S. per year. An estimated 3 million women in the U.S. today are living with breast cancer of which 2 million have been diagnosed with the disease and 1 million have the disease but do not yet know it. Worldwide, it is estimated that 1.2 million new diagnoses and 500,000 deaths from breast cancer will occur this year.
  • Breast cancer often first manifests itself as a painless lump, detectable by self- examination and clinical breast exams including mammograms. Commonly, growth initiates in the lining of the ducts or in the lobules of the breast.
  • Metastasis may occur early or late in the disease progression, although typically metastasis occurs once the cancerous growth reaches a size of about 20 mm.
  • therapies that are effective for long term treatment of breast cancer that has metastasized to lymph nodes or distal sites.
  • vitamin D compounds and analogues are potent inhibitors of malignant cell proliferation and are inducers/stimulators of cell differentiation.
  • U.S. Patent No. 4,391,802 issued to Suda et al. discloses that l ⁇ -hydroxyvitamin D compounds, specifically l ⁇ ,25-dihydroxyvitamin D 3 and l ⁇ -hydroxyvitamin D 3 , possess potent antileukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) to nonmalignant macrophages (monocytes), and are useful in the treatment of leukemia.
  • vitamin D 3 compounds may indeed be highly effective in promoting differentiation in malignant cells in culture, their practical use in differentiation therapy as anticancer agents is severely limited because of their equally high potency as agents affecting calcium metabolism.
  • these same compounds can induce markedly elevated and potentially dangerous blood calcium levels by virtue of their inherent calcemic activity. That is, the clinical use of l ⁇ ,25-dihydroxyvitamin D 3 and other vitamin D 3 analogues as anticancer agents is severely limited by the risk of hypercalcemia.
  • vitamin D compounds with greater specific activity and selectivity of action i.e., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity. It also indicates a need for co-administration agents which can be combined with vitamin D 3 agents, allowing for smaller doses of vitamin D 3 compounds to be used while achieving the same or greater beneficial effect.
  • the present invention includes a method of inhibiting or reducing the hyperproliferative activity of human breast cancer or neoplastic cells.
  • the method includes use of active vitamin D compounds with other anticancer agents to additively or synergistically inhibit abnormal cell growth and/or promote cell differentiation.
  • vitamin D compounds used in combination with various anticancer drugs can give rise to a significantly enhanced cytotoxic or antineoplastic effect on cancerous cells, thus providing an increased therapeutic effect.
  • a significantly increased growth-inhibitory effect is obtained with the above disclosed combinations utilizing lower concentrations of the anticancer drugs compared to the treatment regimes in which the drugs are used alone.
  • Such combinations provide therapy wherein adverse side effects associated with the various anticancer drugs are considerably reduced compared to side effects normally observed with the anticancer drugs used alone in larger doses.
  • such combination therapy allows for a greater antineoplastic effect to be derived from the usual dose of anticancer drugs used in standard treatment regimes, enhancing the effectiveness of the therapy and/or reducing the total number of treatments required.
  • the foregoing are realized in one aspect by providing a pharmaceutical combination comprising a first and second agent.
  • the first agent comprises l ⁇ ,24-dihydroxyvitamin D 2 and the second agent comprises doxorubicin, cisplatin and paclitaxel or combinations thereof.
  • the first and second agents are suitably present in therapeutically effective amounts and agents work synergistically to inhibit the growth of human breast cancer cells.
  • the invention also provides a method of synergistically inhibiting the growth of human breast cancer cells.
  • the method comprises contacting the cells with a first composition which comprises l ⁇ ,24-dihydroxyvitamin D 2 and a second composition which comprises an agent selected from the group consisting of doxorubicin, cisplatin and paclitaxel or combinations thereof.
  • the invention also provides for a combination of vitamin D agents and anticancer agents that work additively.
  • a pharmaceutical combination comprises a first agent which is l ⁇ ,24- dihydroxyvitamin D 2 and a second agent which is selected from the group consisting of busulfan, carboplatin, etoposide, 5-fluorouracil and tamoxifen.
  • the first and second agents have additive properties for inhibiting growth of human breast cancer cells.
  • the invention also provides another pharmaceutical combination for the inhibition of human breast cancer cells.
  • the pharmaceutical combination comprises a therapeutically effective dose of an additive combination of a first agent which is l ⁇ ,24- dihydroxyvitamin D 2 and a second agent which is selected from the group consisting of busulfan, carboplatin, etoposide, 5-fluorouracil and tamoxifen.
  • the invention provides a method of additively inhibiting the growth of human breast cancer cells.
  • the method comprises contacting the cells with a first composition which comprises l ⁇ ,24-dihydroxyvitamin D 2 and a second composition which comprises an agent selected from the group consisting of busulfan, carboplatin, etoposide, 5-fluorouracil and tamoxifen or combinations thereof.
  • Effective amounts of active vitamin D compounds can be administered to patients with cancer or neoplasms.
  • the proliferative activity of the abnormal neoplastic cells is inhibited, reduced, or stabilized, and/or cell differentiation is induced, promoted or enhanced.
  • the effective amounts of vitamin D compound can be given in an administration protocol in a variety of dose ranges depending on the particular need of the patient.
  • One such suitable dose range is a range from .01 ⁇ g to 400 ⁇ g.
  • Another suitable dose range is administered on a daily basis per kilogram of body weight, the dose ranges being from 0.001 ⁇ g/kg/day to 5.0 ⁇ g/kg/day.
  • Another dosing regimen calls for a high dosage, generally 10 ⁇ g/dose or greater up to 400 ⁇ g/dose or greater, given episodically or intermittently.
  • the protocol or dosage regimen in accordance with the present invention provides an improved therapeutic index for active forms of vitamin D analogues compared to administration via conventional regimens.
  • the episodic dosing is also cost effective as a lower quantity of active agent is needed.
  • Administration of the active vitamin D may be prior to, simultaneous with, or after administration of the other therapeutic agents.
  • parenteral administration of the active vitamin D compounds alone or in combination with other agents provides advantages over other treatment modalities.
  • Parenteral administration bypasses the increased calcemic activity that occurs in the gastrointestinal tract from oral administration and reduces incidence or risk of esophagitis.
  • Parenteral dosing also provides for greater compliance and safety because the drugs are generally administered by a health care professional.
  • FIG. 1 shows the growth inhibition of MCF-7 cells by l ⁇ ,24-dihydroxyvitamin D 2 .
  • FIG. 2 shows the growth inhibition of MCF-7 cells by etoposide and l ⁇ ,24 ⁇ dihydroxyvitamin D 2 .
  • FIG. 3 shows an isobologram of etoposide and l ⁇ ,24-dihydroxyvitamin D 2 in MCF- 7 cells.
  • FIG. 4 shows the growth inhibition of MCF-7 cells by etoposide and .1 nM l ⁇ ,24- dihydroxyvitamin D 2 .
  • FIG. 5 shows the growth inhibition of MCF-7 cells by doxorubicin and l ⁇ ,24- dihydroxyvitamin D 2 .
  • FIG. 6 shows an isobologram of doxorubicin and l ⁇ ,24-dihydroxyvitamin D 2 in MCF-7 cells.
  • FIG. 7 shows the growth inhibition of MCF-7 cells by doxorubicin and .01 nM l ⁇ ,24-dihydroxyvitarnin D 2 .
  • FIG. 8 shows the growth inhibition of MCF-7 cells by doxorubicin and .1 nM l ⁇ ,24-dihydroxyvitamin D 2 .
  • FIG. 9 shows the growth inhibition of MCF-7 cells by doxorubicin and 1 nM l ⁇ ,24- dihydroxyvitamin D 2 .
  • FIG. 10 shows the growth inhibition of MCF-7 cells by doxorubicin and 10 nM l ⁇ ,24-dihydroxyvitamin D 2 .
  • FIG. 11 shows the growth inhibition of MCF-7 cells by tamoxifen and l ⁇ ,24- dihydroxyvitamin D 2.
  • FIG. 12 shows an isobologram of tamoxifen and l ⁇ ,24-dihydroxyvitamin D 2 in MCF-7 cells.
  • FIG. 13 shows the growth inhibition of MCF-7 cells by tamoxifen and .01 nM l ⁇ ,24-dihydroxyvitamin D 2 .
  • FIG. 14 shows the growth inhibition of MCF-7 cells by tamoxifen and .1 nM l ⁇ ,24- dihydroxyvitamin D 2 .
  • FIG. 15 shows the growth inhibition of MCF-7 cells by chlorambucil and l ⁇ ,24- dihydroxyvitamin D 2 .
  • FIG. 16 shows an isobologram of chlorambucil and l ⁇ ,24-dihydroxyvitamin D 2 in MCF-7 cells.
  • FIG. 17 shows the growth inhibition of MCF-7 cells by chlorambucil and .1 nM l ⁇ ,24-dihydroxyvitamin D 2 .
  • FIG. 18 shows the growth inhibition of MCF-7 cells by busulfan and l ⁇ ,24- dihydroxyvitamin D 2 .
  • FIG. 19 shows an isobologram of busulfan and l ⁇ ,24-dihydroxyvitamin D 2 in MCF- 7 cells.
  • FIG. 20 shows the growth inhibition of MCF-7 cells by busulfan and .1 nM l ⁇ ,24- dihydroxyvitamin D 2 .
  • FIG. 21 shows combination index values for chemotherapeutic agents and l ⁇ ,24- dihydroxyvitamin D 2 combinations in MCF-7 cells.
  • the present invention includes an effective method for the treatment of neoplastic and hyperplastic diseases.
  • the present invention relates to therapeutic methods for inhibiting, ameliorating or alleviating the hyperproliferative cellular activity of diseases of the breast, e.g., breast cancer, and inducing, enhancing or promoting cell differentiation in the diseased cells.
  • the present invention includes a method of inhibiting or reducing the hyperproliferative activity of human breast cancer cells.
  • the method includes use of active vitamin D compounds with other anticancer agents to additively or synergistically inhibit abnormal cell growth and/or promote cell differentiation.
  • the active vitamin D analogs is l ⁇ ,24-dihydroxyvitmin D 2 .
  • additives means that the total inhibitory effect of the agents administered is approximately the sum of their individual inhibitory effects.
  • the term "synergistically inhibits” means that the total inhibitory effect of the agents administered is greater than the sum of the individual inhibitory effects of the agents.
  • activated vitamin D or “active vitamin D” is intended to refer to a vitamin D compound or analogue that has been hydroxylated in at least the C-I position of the A ring of the molecule and either the compound itself or its metabolites in the case of a prodrug, such as lce-hydroxyvitamin D 2 , binds the vitamin D receptor (VDR).
  • prodrugs Such compounds undergo further hydroxylation in vivo and their metabolites bind the VDR.
  • alkyl alkenyl acyl, or cycloalkyl
  • lower as a modifier for alkyl, alkenyl acyl, or cycloalkyl is meant to refer to a straight or branched, saturated or unsaturated hydrocarbon radical having 1 to 4 carbon atoms.
  • hydrocarbon radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl, isobutenyl, isopropenyl, formyl, acetyl, propionyl, butyryl or cyclopropyl.
  • aromatic acyl is meant to refer to a unsubstituted or substituted benzoyl group.
  • hydrocarbon moiety refers to a lower alkyl, a lower alkenyl, a lower acyl group or a lower cycloalkyl, i.e., a straight or branched, saturated or unsaturated CpC 4 hydrocarbon radical.
  • contacting is used herein interchangeably with the following: combined with, added to, mixed with, passed over, incubated with etc.
  • compounds of present invention can be “administered” by any conventional method such as, for example, parenteral, oral, topical and inhalation routes as described herein.
  • the present invention includes a method of treating malignant breast cells (i.e., inhibiting or reducing their hyperproliferative activity and/or inducing and enhancing their differentiation) with an effective amount of a vitamin D analog, co-administered with various inhibitory agents such that the combination of the vitamin D analog and inhibitory agent provides additive or synergistic effects in the inhibition of hyperproliferative activity of the breast cancer cells, i.e., the cells are treated or contacted with both agents.
  • co-administration is meant to refer to a combination therapy by any administration route in which two or more agents are administered to cells, to a patient or to a subject. Co-administration of agents may be referred to as combination therapy or combination treatment.
  • the agents may be the same dosage formulations or separate formulations.
  • the active agents can be administered concurrently, or they each can be administered at separately staggered times.
  • the agents may be administered simultaneously or sequentially, as long as they are given in a manner sufficient to allow both agents to achieve effective concentrations in the body.
  • the agents may be administered by different routes, e.g., one agent may be administered intravenously while a second agent is administered intramuscularly, intravenously or orally.
  • the agents also may be in an admixture, as, for example, in a single tablet.
  • one agent may directly follow administration of the other or the agents may be give episodically, i.e., one can be given at one time followed by the other at a later time, e.g., within a week.
  • An example of a suitable co ⁇ administration regimen is where an active vitamin D compound is administered from 0.5 to 7 days prior to administration of a cytotoxic or other therapeutic agent.
  • vitamin D analog and second anticancer agent Depending on the combination of the particular vitamin D analog and second anticancer agent, and other factors such as concentration and amount of the agents, additive, synergistic or antagonistic inhibiting growth effects on human breast cancer cells can be found.
  • l ⁇ ,24-dihydroxyvitamin D 2 when utilized in combination with the agent doxorubicin, cisplatin and paclitaxel can synergistically inhibits the growth of human breast cancer cells.
  • lo;24-dihydroxyvitamin D 2 can also be utilized with a second composition to additively inhibit the growth of human breast cancer cells.
  • Such second compositions include busulfan, carboplatin, etoposide, 5-fluorouracil and tamoxifen and combinations thereof.
  • the effective amounts of vitamin D compound can be given in an administration protocol in a variety of dose ranges depending on the particular need of the patient.
  • One such suitable dose range is administered on a daily basis per kilogram of body weight, the dose ranges being from 0.001 ⁇ g/kg/day to 5.0 ⁇ g/kg/day.
  • Another dosing regimen calls for a high dosage, generally 10 ⁇ g/dose or greater up to 400 ⁇ g/dose or greater, given episodically or intermittently.
  • Such protocols or dosage regimens provide an improved therapeutic index for active forms of vitamin D analogues compared to administration via conventional regimens.
  • the episodic dosing is also cost effective as less active agent is needed.
  • each single dose is sufficient to upregulate vitamin D hormone receptors in target cells. It is believed that continuous dosing is not required because the binding and upregulation by vitamin D compounds is sufficient to initiate the cascade of intracellular metabolic processes occurring with receptor binding. Intermittent dosing reduces the risk of hypercalcemia, and thus, the method in accordance with the present invention can be used to treat hyperproliferative diseases by administering any active vitamin D compound. At the same time, it is contemplated that the risk of hypercalcemia can be further mitigated if the active vitamin D compound is a hypocalcemic active vitamin D compound.
  • the intermittent dose regimen can be used to effect any therapeutic effect that is attributable to active vitamin D., e.g., antiproliferative activity, reduction of loss of bone mass, etc.
  • antiproliferative activity the value of the intermittent dosing is that antihyperproliferative activity and upregulation of vitamin D receptors occurs with a single dose without the side effects of hypercalcemia and hypercalciuria that occur with recurrent daily dosing.
  • the episodic dose can be a single dose or, optionally, divided into 2-4 subdoses which, if desired, can be given, e.g., twenty minutes to an ' hour apart until the total dose is given.
  • the compounds in accordance with the present invention are administered in an amount that raises serum vitamin D levels to a supraphysiological level for a sufficient period of time to induce differentiation or regression of a tumor or neoplasm without causing hypercalcemia or with substantially reduced risk of hypercalcemia.
  • the properties of the hypocalcemic vitamin D compounds are particularly beneficial in permitting such supraphysiologic levels.
  • the present invention relates to a method of co-administration of active vitamin D compounds with an anticancer or antineoplastic agent.
  • Therapeutic antihyperproliferative benefits are achieved with intermittent dosing of active vitamin D with cytotoxic, i.e., other chemotherapeutic or antineoplastic, agents.
  • cytotoxic i.e., other chemotherapeutic or antineoplastic
  • Many antineoplastic or cytotoxic agents must be delivered through a parenteral route of administration, and thus, a protocol of injectable active vitamin D and antineoplastic agent can be set up on a routine basis.
  • active vitamin D and antineoplastic agents can be prior to, after or simiiitanerms ⁇ with each other
  • a high dose active vitamin D upregulates the receptors, and primes .and promotes cell differentiation.
  • Such upregulation and priming potentially permits less cytotoxic or antineoplastic agent than would typically be required if the cytotoxic agent were administered alone.
  • Dosages for a given patient can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the subject compounds and of a known agent, such as by means of an appropriate conventional pharmacological protocol.
  • a physician of ordinary skill can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition.
  • Optimal precision in achieving concentrations of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • the dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that an efficacious dosage is obtained.
  • the active ingredient is administered to patients (animal and human) in need of treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the active vitamin D analogs and inhibitory agents can be co-administered separately at the same time, at proximate times, or can be delivered simultaneously in an admixture. Both the vitamin D analog, the inhibitory agent, or the admixed combination of the two can be employed in admixtures with conventional excipients, e.g., pharmaceutically acceptable carrier substances suitable for enteral (e.g., oral) or parenteral application which do not deleteriously react with the active compounds.
  • conventional excipients e.g., pharmaceutically acceptable carrier substances suitable for enteral (e.g., oral) or parenteral application which do not deleteriously react with the active compounds.
  • Active vitamin D compounds can be formulated in pharmaceutical compositions in a conventional manner using one or more conventional excipients, which do not deleteriously react with the active compounds, e.g., pharmaceutically acceptable carrier substances suitable for enteral administration (e.g., oral), parenteral, topical, buccal or rectal application, or by administration by inhalation or insufflation (e.g., either through the mouth or the nose)
  • pharmaceutically acceptable carrier substances suitable for enteral administration (e.g., oral), parenteral, topical, buccal or rectal application, or by administration by inhalation or insufflation (e.g., either through the mouth or the nose)
  • acceptable carriers for pharmaceutical formulation include, but are not limited to, water, salt solutions, alcohols, gum arabic, vegetable oils (e.g., almond oil, corn oil, cottonseed oil, peanut oil, olive oil, coconut oil), mineral oil, fish liver oils, oily esters such as Polysorbate 80, polyethylene glycols, gelatine, carbohydrates (e.g., lactose, amylose or starch), magnesium stearate, talc, silicic acid, viscous paraffin, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
  • vegetable oils e.g., almond oil, corn oil, cottonseed oil, peanut oil, olive oil, coconut oil
  • mineral oil e.g., fish liver oils
  • oily esters such as Polysorbate 80
  • polyethylene glycols e.g., gelatine
  • carbohydrates e.g., lactose, am
  • parenteral e.g., injectable, dosage form.
  • Using the parenteral route of administration allows for bypass of the first pass of active vitamin D compound through the intestine, thus avoiding stimulation of intestinal calcium absorption, and further reduces the risk of esophageal irritation which is often associated with high dose oral administration.
  • an injectable route of administration is typically done by a health care professional, the dosing can be more effectively controlled as to precise amount and timing.
  • Parenteral administration suitably includes subcutaneous, intramuscular, or intravenous injection, nasopharyngeal or mucosal absorption, or transdermal absorption.
  • the vitamin D compounds may also be given by direct injection into the tumor by intraarterial delivery or delivery via the portal vein.
  • the injectable compositions may take such forms as sterile suspensions, solutions, or emulsions in oily vehicles (such as coconut oil, cottonseed oil, sesame oil, peanut oil or soybean oil) or aqueous vehicles, and may contain various formulating agents.
  • the active ingredient may be in powder (lyophilized or non-lyophilized) form for reconstitution at the time of delivery with a suitable vehicle, such as sterile water.
  • the carrier is typically sterile, pyrogen-free water, saline, aqueous propylene glycol, or another injectable liquid, e.g., peanut oil for intramuscular injections.
  • various buffering agents, preservatives, suspending, stabilizing or dispensing agents, surface-active agents and the like can be included.
  • Aqueous solutions may be suitably
  • Aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
  • the oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • the compounds formulated for parenteral administration by injection may be administered, by bolus injection or continuous infusion.
  • Formulations for injection may be conveniently presented in unit dosage form, e.g., in ampoules or in multi-dose, multi-use containers, with an added preservative.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., a sparingly soluble salt.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium o+oof o+ ⁇ f n l ⁇ > r ⁇ f oi1- ⁇ r» ⁇ V ( e*.
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium o+oof o+ ⁇ f n l ⁇ > r ⁇ f oi1- ⁇ r» ⁇ V ( e*.
  • the tablets may be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p- hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
  • Preparations for oral administration may also be suitably formulated to give controlled release of the active compound.
  • Many controlled release systems are known in the art.
  • compositions may take the form of tablets, lozenges or absorption wafers formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin, for use in an inhaler or insufflator may be formulated containing a powder mix of the active compound and a suitable powder base such as lactose or starch.
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories containing conventional suppository bases or retention enemas.
  • rectal or vaginal compositions such as suppositories containing conventional suppository bases or retention enemas.
  • These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature (for example, 10° C to 32° C) but liquid at the rectal temperature, and will melt in the rectum or vagina to release the active ingredient.
  • a suitable non-irritating excipient which is solid at room temperature (for example, 10° C to 32° C) but liquid at the rectal temperature, and will melt in the rectum or vagina to release the active ingredient.
  • suitable non-irritating excipient which is solid at room temperature (for example, 10° C to 32° C) but liquid at the rectal temperature, and will melt in the rectum or vagina to release the active ingredient.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pharmaceutical preparations can be sterilized and, if desired, be mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or one or more other active compounds, for example, conjugated estrogens or their equivalents, anti-estrogens, calcitonin, bisphosphonates, calcium supplements, cobalamin, pertussis toxin, boron, and antihypercalcemic agents.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or one or more other active compounds, for example, conjugated estrogens or their equivalents, anti-estrogens, calcitonin, bisphosphonates, calcium supplements, cobalamin, pertussis toxin, boron,
  • VDR BINDING ANALYSES 1 a,24-dihydroxyvitamin D 2 [ 10,24-(OH) 2 D 2 ]
  • the affinity of 10,24-(OH) 2 D 2 for the mammalian vitamin D receptor (VDR) was assessed using a commercially available kit of bovine thymus VDR and standard 1,25- (OH) 2 D 3 solutions from Incstar (Stillwater, Minnesota).
  • the half-maximal binding of chemically synthesized 10,24-(OH) 2 D 2 was approximately 150 pg/ml whereas that of 10,25-(OH) 2 D 3 was 80 pg/ml.
  • the l ⁇ ,24-(OH) 2 D 2 had a very similar affinity for bovine thymus VDR as did 10,25-(0H) 2 D 3 , indicating that 10,24-(OH) 2 D 2 has potent biological activity.
  • Example 2 1 ⁇ ,24-dihydroxyvitamin D 2 [ 10,24-(OH) 2 D 2 ]
  • VDR binding of vitamin D compounds by breast cells is demonstrated using the techniques of Skowronski et al., 136 Endocrinology (1995) 20-26, which is incorporated herein by reference.
  • Breast-derived cell lines are cultured to near confluence, washed and harvested by scraping. Cells are washed by centrifugation, and the cell pellet resuspended in a buffered salt solution containing protease inhibitors. The cells are disrupted by sonication while cooling on ice. The supernatant obtained from centrifuging the disrupted cells at 207,000 x g for 35 min at 4°C is assayed for binding.
  • Example 3 l ⁇ ,24(S)-dmydroxyvitamin D 2 and l ⁇ ,24(R)-dihydroxy-vitamin D 2 10,24(S)-(OH) 2 D 2 and 10,24(R)-(OH) 2 D 2 ]
  • One plasmid contained the gene for Growth Hormone (GH) under the control of the vitamin D responsive element (VDRE) and the other plasmid contained the structural gene for the vitamin D receptor (VDR).
  • GH Growth Hormone
  • VDRE vitamin D responsive element
  • VDR vitamin D receptor
  • the cell line MCF-7 is seeded in six-well tissue culture plates at a density of about 50,000 cells/plate. After the cells have attached and stabilized, about 2-3 days, the medium is replenished with medium containing vehicle or the active vitamin D analogue 10,24-(OH) 2 D 2 , at concentrations from 10 '11 M to 10 "7 M. Medium containing test analogue or vehicle is replaced every three days.
  • the medium is removed, the cells are rinsed, precipitated with cold 5% trichloroacetic acid, and washed with cold ethanol.
  • the cells are solubilized with 0.2 N sodium hydroxide, and the amount of DNA determined by standard procedures. The results show that cultures incubated with 10,24-(OH) 2 D 2 have significantly fewer cells than the control cultures.
  • Patients with a known vitamin D receptor positive tumor participate in an open-label study of an active vitamin D compound in accordance with the present invention.
  • Patients are placed on a reduced calcium diet prior to treatment, to help minimize intestinal absorption and allow ever higher doses of the active vitamin D.
  • This reduced calcium diet may be continued for the duration of treatment, and for one week after the last dose of the active vitamin D.
  • the diet ideally restricts daily calcium intake to 400-500 mg.
  • Patients also discontinue use of any vitamin D supplements or vitamin D replacement therapies.
  • Each patient is also asked to drink 4-6 cups of fluid more than usual intake to assure adequate oral hydration.
  • Each subject is monitored at regular intervals for: (1) hypercalcemia, hyperphosphatemia, hypercalciuria, hyperphosphaturia and other toxicity; (2) evidence of changes in the progression of metastatic disease; and (3) compliance with the prescribed test drug dosage.
  • a non-daily, episodic dosing regimen is used, e.g., 10 ⁇ g or 20 ⁇ g per dose to about 200 ⁇ g or 400 ⁇ g/dose given once a week to once every 12 weeks.
  • the route of administration can vary from oral to intravenous to regional delivery (e.g., arterial infusion, via the portal vein). Oral is typically the easiest route; however, intravenous administration is advantageous for high dosing because, for example, it generally avoids hypercalcemia due to stimulation of calcium absorption in the intestine.
  • Regional delivery also permits high dosing and generally avoids any hypercalcemia. Although, in the case of the hypocalcemic compounds of the present invention, these compounds are inherently of low risk of producing hypercalcemia.
  • Example 5 The method of Example 5 is used is used to treat patients with breast cancer. After 18 months of treatment, the progress of the cancer shows stable disease or partial remission.
  • Example 7 1 o,24-dihydroxy vitamin D 2 [ 10,24-(OH) 2 D 2 ]
  • Qualified patients are at least 40 years old. On admission to the study, patients begin a course of therapy with oral 10,24-(OH) 2 D 2 lasting 26 weeks, while discontinuing any previous use of calcium supplements, vitamin D supplements, and vitamin D hormone replacement therapies. During treatment, the patients are monitored at regular intervals for:
  • hypercalcemia hyperphosphatemia
  • hypercalciuria hyperphosphaturia
  • hyperphosphaturia hyperphosphaturia
  • other toxicity evidence of changes in the progression of metastatic disease
  • compliance with the prescribed test drug dosage (1) hypercalcemia, hyperphosphatemia, hypercalciuria, hyperphosphaturia and other toxicity; (2) evidence of changes in the progression of metastatic disease; and (3) compliance with the prescribed test drug dosage.
  • the maximal tolerated dosage (MTD) of daily oral 10,24-(0H) 2 D 2 is determined by administering progressively higher dosages to successive groups of patients. All doses are administered in the morning before breakfast.
  • the first group of patients is treated with 25.0 ⁇ g of l ⁇ ,24-(OH) 2 D2. Subsequent groups of patients are treated with 50.0, 75.0 and 100.0 ⁇ g/day. Dosing is continued uninterrupted for the duration of the study unless serum calcium exceeds 11.6 mg/dL, or other toxicity of grade 3 or 4 is observed, in which case dosing is held in abeyance until resolution of the observed toxic effect(s) and then resumed at a level which has been decreased by 10.0 ⁇ g.
  • results from the first phase of the study show that the MTD for 10,24-(OH) 2 D 2 is above 20.0 ⁇ g/day, a level which is 10- to 40-fold higher than can be achieved with l ⁇ ,25-(OH) 2 D 3 .
  • Analysis of blood samples collected at regular intervals from the participating patients reveal that the levels of circulating 10,24-(0H) 2 D 2 increase proportionately with the dosage administered, rising to maximum levels well above 100 pg/mL at the highest dosages, and that circulating levels of lo,25-(OH) 2 D 3 are suppressed, often to undetectable levels. Serum and urine calcium are elevated in a dose responsive manner. Patients treated with the MTD of 10,24-(OH) 2 D 2 for at least six months report that bone pain associated with metastatic disease is significantly diminished.
  • CAT scans, X-rays and bone scans used for evaluating the progression of metastatic disease show stable disease or partial remission in many patients treated at the lower dosage, and stable disease and partial or complete remission in many patients treated at the higher dosage.
  • Vitamin D agents are tested for synergistic and additive interactions with anticancer drugs on human MCF-7 cancer cell lines.
  • MCF-7 cells were plated in 96-well plates in triplicate and allowed to grow 48 hours. The medium was removed and replaced with medium containing vehicle (0.1% Ethanol), vitamin D compound 1,24(OH) 2 D 2 , and/or chemotherapeutic agents (busulfan, 5-fluorouracil, paclitaxel, tamoxifen, cisplatin, carboplatin, doxorubicin, chlorambucil, or etoposide). Cells were allowed to grow for an additional 6 days with media changed on day 3.
  • chemotherapeutic agents busulfan, 5-fluorouracil, paclitaxel, tamoxifen, cisplatin, carboplatin, doxorubicin, chlorambucil, or etoposide.
  • Example 9 Growth Inhibition of MCF-7 Cells by 1,24(OH) 2 D 2 alone.
  • MCF-7 cells were plated in 96-well plates in triplicate and allowed to grow 48 hours. The medium was removed and replaced with medium containing vehicle (0.1% Ethanol) and 1,24(OH) 2 D 2 in various concentrations. Cells were allowed to grow for an additional 6 days with media changed on day 3. Cell number was then determined by a colorimetric MTS assay and expressed as a % of change from control cells grown in vehicle only. The growth inhibition of the cells by 1,24(OH) 2 D 2 are shown in FIG. 1.
  • Example 10 Growth inhibition of MCF-7 cells by etoposide and with 1,24(OH) 2 D 2 .
  • MCF-7 cells were plated in 96-well plates in triplicate and allowed to grow 48 hours. The medium was removed and replaced with medium containing vehicle (Ethanol), 1,24(OH) 2 D 2 in various concentrations, and etoposide in various concentrations. Cells were allowed to grow for an additional 6 days with media changed on day 3. Cell number was then determined by a colorimetric MTS assay and expressed as a % of change from control cells grown in vehicle only.
  • FIG. 2 shows the percent inhibition of MCF-7 cells of etoposide alone or in combination with various concentrations of 1,24(OH) 2 D 2 . ID30 values (dose required to inhibit proliferation by 30%) were calculated to compare growth inhibitory effects of the compounds alone and in combination.
  • Isobologram analysis was used to characterize the interaction between 1,24(OH) 2 D 2 and etoposide as synergistic, additive, or antagonistic.
  • the isobologram is shown in FIG. 3, and shows that etoposide in the concentration range of about 0 to 0.2 ⁇ M when combined with 1,24(OH) 2 D 2 of various concentrations can provide an additive or mild synergistic effect. This effect can also be seen in FIG. 4.
  • the addition columns show the amount of inhibition predicted if the combination of etoposide and 1,24(OH) 2 D 2 simply had an additive effect on each other.
  • the growth inhibition chart of FIG. 4 shows that the combination of etoposide in concentrations of .1 ⁇ M, 1 ⁇ M, 10 ⁇ M and 100 ⁇ M with O.lnM of 1,24(OH) 2 D 2 produces additive to mild synergistic growth inhibition.
  • Example 11 Growth inhibition of MCF-7 cells by doxorubicin and with 1 ,24(OH) 2 D 2 .
  • MCF-7 cells were plated in 96-well plates in triplicate and allowed to grow 48 hours. The medium was removed and replaced with medium containing vehicle (Ethanol), 1,24(OH) 2 D 2 in various concentrations, and doxorubicin in various concentrations. Cells were allowed to grow for an additional 6 days with media changed on day 3. Cell number was then determined by a colorimetric MTS assay and expressed as a % of change from control cells grown in vehicle only.
  • FIG. 5 shows the percent inhibition of MCF-7 cells of doxorubicin alone or in combination with various concentrations of 1,24(OH) 2 D 2 .
  • ID30 values (dose required to inhibit proliferation by 30%) were calculated to compare growth inhibitory effects of the compounds alone and in combination.
  • Isobologram analysis was used to characterize the interaction between 1,24(OH) 2 D 2 and doxorubicin as synergistic, additive, or antagonistic.
  • the isobologram is shown in FIG. 6, and shows that doxorubicin in the concentration range of about 0 to 0.15 ⁇ M when combined with 1,24(OH) 2 D 2 of various concentrations can provide a synergistic effect. This effect can also be seen in FIG.'s 7-10.
  • FIG.'s 7-10 show that in certain concentrations, doxorubicin can have a synergistic effect when combined with 1,24(OH) 2 D 2 .
  • FIG. 7-10 the addition columns show the amount of inhibition predicted if the combination of doxorubicin and 1,24(OH) 2 D 2 simply had an additive effect on each other.
  • the growth inhibition chart of FIG. 7 shows that the combination of doxorubicin in concentrations of 0.01 ⁇ M, 0.1 ⁇ M, 1 ⁇ M, 10 ⁇ M and 100 ⁇ M with 0.01 nM of 1,24(OH) 2 D 2 produces synergistic growth inhibition.
  • the growth inhibition chart of FIG. 8 shows that the combination of doxorubicin in concentrations of 1 ⁇ M, 10 ⁇ M and 100 ⁇ M with 0.1 nM of 1,24(OH) 2 D 2 produces synergistic growth inhibition.
  • the growth inhibition chart of FIG. 7 shows that the combination of doxorubicin in concentrations of 0.01 ⁇ M, 0.1 ⁇ M, 1 ⁇ M, 10 ⁇ M and 100 ⁇ M with 0.01 nM of 1,24(OH) 2 D 2 produces synergistic growth inhibition.
  • Example 9 shows that the combination of doxorubicin in concentrations of 0.001 ⁇ M, 0.01 ⁇ M, 0.1 ⁇ M, l ⁇ M, 10 ⁇ M and 100 ⁇ M with 1 nM of 1,24(OH) 2 D 2 produces synergistic growth inhibition.
  • the growth inhibition chart of FIG. 10 shows that the combination of doxorubicin in concentrations of 0.01 ⁇ M, 0.01 ⁇ M, l ⁇ M, 10 ⁇ M and 100 ⁇ M with 10 nM of 1,24(OH) 2 D 2 produces synergistic growth inhibition.
  • Example 12 Growth inhibition of MCF-7 cells by tamoxifen and with 1,24(OH) 2 D 2 .
  • MCF-7 cells were plated in 96-well plates in triplicate and allowed to grow 48 hours. The medium was removed and replaced with medium containing vehicle (Ethanol), 1,24(OH) 2 D 2 in various concentrations, and tamoxifen in various concentrations. Cells were allowed to grow for an additional 6 days with media changed on day 3. Cell number was then determined by a colorimetric MTS assay and expressed as a % of change from control cells grown in vehicle only.
  • FIG. 11 shows the percent inhibition of MCF-7 cells of tamoxifen alone or in combination with various concentrations of 1,24(OH) 2 D 2 . ED30 values (dose required to inhibit proliferation by 30%) were calculated to compare growth inhibitory effects of the compounds alone and in combination.
  • Isobologram analysis was used to characterize the interaction between 1,24(OH) 2 D 2 and tamoxifen as synergistic, additive, or antagonistic.
  • the isobologram is shown in FIG. 12.
  • the addition columns show the amount of inhibition predicted if the combination of tamoxifen and 1,24(OH) 2 D 2 simply had an additive effect on each other.
  • the growth inhibition chart of FIG. 13 shows that the combination of tamoxifen in concentrations of 10 ⁇ M and 100 ⁇ M with 0.01 nM of 1,24(OH) 2 D 2 produces additive to mild synergistic growth inhibition.
  • the growth inhibition chart of FIG. 14 shows that the combination of tamoxifen in concentrations of 10 ⁇ M and 100 ⁇ M with 0.1 nM of 1,24(OH) 2 D 2 produces additive to mild synergistic growth inhibition.
  • Example 13 Growth inhibition of MCF-7 cells by chlorambucil and with 1,24(OH) 2 D 2 .
  • MCF-7 cells were plated in 96-well plates in triplicate and allowed to grow 48 hours. The medium was removed and replaced with medium containing vehicle (Ethanol), 1,24(OH) 2 D 2 in various concentrations, and chlorambucil in various concentrations. Cells were allowed to grow for an additional 6 days with media changed on day 3. Cell number was then determined by a colorimetric MTS assay and expressed as a % of change from control cells grown in vehicle only.
  • FIG. 15 shows the percent inhibition of MCF-7 cells of chlorambucil alone or in combination with various concentrations of 1 ,24(OH) 2 D 2 .
  • ID30 values (dose required to inhibit proliferation by 30%) were calculated to compare growth inhibitory effects of the compounds alone and in combination.
  • Isobologram analysis was used to characterize the interaction between 1,24(OH) 2 D 2 and chlorambucil as synergistic, additive, or antagonistic.
  • the isobologram is shown in FIG. 16.
  • FIG. 17 shows that in certain concentrations, chlorambucil can have an additive effect when combined with 1,24(OH) 2 D 2 .
  • the addition columns show the amount of inhibition predicted if the combination of chlorambucil and 1 ,24(OH) 2 D 2 simply had an additive effect on each other.
  • the growth inhibition chart of FIG. 17 shows that the combination of chlorambucil in various concentrations produces antagonistic to mild additive growth inhibition.
  • Example 14 Growth inhibition of MCF-7 cells by busulfan and 1,24(OH) 2 D 2 .
  • MCF-7 cells were plated in 96-well plates in triplicate and allowed to grow 48 hours. The medium was removed and replaced with medium containing vehicle (Ethanol), 1,24(OH) 2 D 2 in various concentrations, and busulfan in various concentrations. Cells were allowed to grow for an additional 6 days with media changed on day 3. Cell number was then determined by a colorimetric MTS assay and expressed as a % of change from control cells grown in vehicle only.
  • FIG. 18 shows the percent inhibition of MCF-7 cells of busulfan alone or in combination with various concentrations of 1,24(OH) 2 D 2 . ID30 values (dose required to inhibit proliferation by 30%) were calculated to compare growth inhibitory effects of the compounds alone and in combination.
  • Isobologram analysis was used to characterize the interaction between 1,24(OH) 2 D 2 and busulfan as synergistic, additive, or antagonistic.
  • the isobologram is shown in FIG. 19.
  • the addition columns show the amount of inhibition predicted if the combination of busulfan and 1,24(OH) 2 D 2 simply had an additive effect on each other.
  • the growth inhibition chart of FIG. 20 shows that the combination of busulfan in concentrations of 100 ⁇ M with 0.1 nM of 1,24(OH) 2 D 2 produces mild synergistic growth inhibition.
  • Example 15 Combination Index (CI) values for chemotherapeutic drugs and 1,24(OH) 2 D 2 combinations in MCF-7 cells.
  • 1,24(OH) 2 D 2 was dosed in combination with individual anticancer agents at several different molar ratios.
  • the degree of interaction between two drugs was calculated using the combination index, according to the isobologram equation:
  • CI (Ii Z D 1 + d 2 / D 2 .
  • di and d 2 represent the doses of drug 1 and drug 2 that, when given ' in combination, produce a specific response
  • Di and D 2 represent the doses of drug 1 and drug 2 when given individually, produce the same effect.
  • Drug interactions determined by the Combination Index were classified according to the following criteria:

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Abstract

L'invention concerne des méthodes thérapeutiques destinées à inhiber, améliorer ou soulager l'activité cellulaire hyperproliférative de maladies du sein, par exemple, de cancer du sein, lesdites méthodes consistant à administrer à un patient le nécessitant un analogue de vitamine D actif et un autre agent anticancéreux. La différenciation cellulaire est favorisée, induite ou améliorée sans provoquer, chez le patient, d'hypercalcémie et d'hypercalciurie limitant les doses.
PCT/US2005/023259 2004-06-30 2005-06-29 Methode de traitement de cancer du sein au moyen d'un melange d'analogues de vitamine d et d'autres agents WO2006004917A2 (fr)

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